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Enhancing Gasdermin-induced tumor pyroptosis through preventing ESCRT-dependent cell membrane repair augments

Zhaoting Li1,2,3, Fanyi Mo1, Yixin Wang1,2,3

  • 1Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, Madison, WI, 53705, USA.

Nature Communications
|October 24, 2022
PubMed

Insights

Blocking calcium influx-mediated membrane repair enhances gasdermin-induced tumor cell pyroptosis. This strategy, using nanoparticles and a bacteria-based delivery system, boosts anti-tumor immune responses for effective cancer therapy.

Area of Science:

  • Oncology
  • Immunology
  • Biotechnology

Background:

  • Gasdermin-induced pyroptosis in tumor cells initiates anti-tumor immunity via cytokine release.
  • Endosomal sorting complexes required for transport (ESCRT) III-mediated membrane repair limits pyroptosis by resealing gasdermin pores.
  • Targeting tumor cell membrane repair is crucial for enhancing pyroptosis-based cancer therapies.

Purpose of the Study:

  • To investigate the synergistic effect of blocking ESCRT III-mediated membrane repair and gasdermin-induced pyroptosis for enhanced anti-tumor immunity.
  • To develop novel delivery systems for simultaneous administration of pyroptosis inducers and membrane repair inhibitors.

Main Methods:

  • Utilized a bacteria-based delivery system (VNP-GD) for intracellular delivery of Gasdermin D (GSDMD).
  • Developed biodegradable nanoparticles (EI-NP) for sustained release of a calcium chelator to block ESCRT III-dependent membrane repair.
  • Formulated injectable hydrogels and lyophilized hydrogel-based cell patches for peritumoral and implantation administration.

Main Results:

  • Blocking calcium influx-triggered ESCRT III repair significantly enhanced GSDMD-induced tumor pyroptosis.
  • The combined VNP-GD and EI-NP system demonstrated synergistic effects in triggering pyroptosis and augmenting anti-tumor immune responses.
  • Hydrogel formulations provided sustained release, enabling effective treatment of primary, metastatic, and inoperable tumors.

Conclusions:

  • Simultaneous inhibition of ESCRT III-mediated membrane repair and induction of pyroptosis represents a promising strategy for cancer immunotherapy.
  • The developed nanoparticle and bacteria-based delivery systems offer a versatile platform for synergistic tumor cell killing and immune stimulation.
  • This approach holds potential for treating various tumor types, including those resistant to conventional therapies.

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